Muscarinic antagonists and combinations thereof for the treatment of airway disease in horses

ABSTRACT

The invention relates to the field of medicine, in particular to the field of veterinary medicine. The invention specifically relates to muscarinic antagonists (including long acting muscarinic antagonists (LAMAs)) for the treatment of airway disease, such as pulmonary disease, preferably recurrent airway obstruction (RAO), summer pasture associated obstructive pulmonary disease (SPAOPD), and inflammatory airway disease (IAD) in animals, preferably equines such as horses.

FIELD OF THE INVENTION

The invention relates to the field of medicine, in particular to thefield of veterinary medicine. The invention specifically relates tomuscarinic antagonists (including long acting muscarinic antagonists(LAMAs)) for the treatment of airway disease, such as pulmonary disease,preferably recurrent airway obstruction (RAO), summer pasture associatedobstructive pulmonary disease (SPAOPD), and inflammatory airway disease(IAD) in animals, preferably equines such as horses.

BACKGROUND INFORMATION

Equine airway disease is a prominent disease in many horses. It can bedivided into the diseases of the upper and lower airways. There are anumber of equine lower airway diseases with noninfectious origin such asRAO (or heaves or equine chronic obstructive pulmonary disease), IAD,SPAOPD and exercise induced pulmonary hemorrhage (EIPH). The latter istypically diagnosed in racehorses. RAO, IAD and SPAOPD are diseases withan allergic background. Rarely diagnosed additional lower airwaydisorders are granulomatous, neoplastic and interstitial pneumonias. Theinfectious diseases of the lower airway include bronchitis, pneumonia,pleuritis or a combination of these caused by viral, bacterial, fungaland parasitic agents (Kutasi et al., 2011).

Common phenotypic manifestations of airway disease in horses includecoughing, nasal discharge, increased respiratory effort and poorperformance or exercise intolerance. Additionally, fever, depression,decreased appetite and weight loss can be observed in infectious airwaydiseases (Couetil et al., 2007 and Kutasi et al., 2011).

Equine airway diseases with an allergic background cannot be cured butonly kept asymptomatic. The known therapies for these horses includechanges in the environment and the administration of different drugs.The aim of the change in the stable environment is to improve airwayquality and to reduce the allergen exposure of the horses, which mighttrigger the exacerbations of RAO, SPAOPD and IAD. The following drugsare used for the treatment of airway diseases with non-infectiousorigin: glucocorticoids, bronchodilators (beta-2 adrenoceptor agonistsand muscarinic antagonists), and mucosolvants (dembrexin andacetylcystein). In addition, antibiotics are administered for infectiousairway diseases. Prominent side effects of these standard therapies aretachycardia, mydriasis, change in the hydration status of the mucousmem-branes and colic for bronchodilators and adrenocortical suppression(reduction in the blood serum levels of cortisol), laminitis,hepatopathy, muscle wasting, altered bone metabolism, increasedsusceptibility to infection (neutrophilia, lymphopenia) and decreasedantibody response to vaccination for glucocorticoids (Couetil et al.,2007, Dauvillir et al., 2011).

The problem underlying the present invention is to provide a medicationfor horses which allows the treatment of airway disease in horses with aquick onset of action while reducing the risk of side effects for thetreated animals.

BRIEF SUMMARY OF THE INVENTION

It has been surprisingly found that muscarinic antagonists, especiallylong-acting muscarinic antagonists (LAMAs), preferably a LAMA of theformula I, are particularly advantageous for the use in a method oftreating an airway disease in equines, preferably horses.

Preferred LAMAs have the following general structure:

wherein A denotes a double-bonded group selected from among

X— denotes an anion with a single negative charge, R1 and R2 denoteC1-C4-alkyl, which may optionally be substituted by hydroxy or halogen;R3, R4, R5 and R6, which may be identical or different, denote hydrogen,C1-C4-alkyl, C1-C4-alkyloxy, hydroxy, CF3, CN, NO2 or halogen; R7denotes hydrogen, C1-C4-alkyl, C1-C4-alkyloxy, C1-C4-alkylene-halogen,halogen-C1-C4-alkyloxy, C1-C4-alkylene-OH, CF3,—C1-C4-alkylene-C1-C4-alkyloxy, —O—COC1-C4-alkyl,—O—COC1-C4-alkyl-halogen, —O—COCF3 or halogen, optionally in the form ofthe individual optical isomers, mixtures of the individual enantiomersor racemates thereof, while if A denotes

R¹ and R² denote methyl and ³, R⁴, R⁵ and R⁶ denote hydrogen, R⁷ cannotalso be hydrogen.

Further, it has been surprisingly found that especially LAMA 1 oranother pharmaceutically acceptable salt of the cation thereof or acomposition comprising LAMA 1 or a pharmaceutically acceptable saltthereof is particularly advantageous for the use in a method of treatingan airway disease in equines, preferably horses.

An advantage of the present invention is the quick start of the effectafter administration lasting up to several hours (see for example,Example 7). In addition, the once daily treatment with LAMA 1 for oneweek is comparable to the significant improvement in lung function afterthe twice daily administration of clenbuterol for one week. This isaccompanied with a significant increase in the arterial blood pH and asignificant decrease in the partial pressure of carbon dioxide (paCO₂)in the arterial blood, which are observed only after the administrationof LAMA 1 for one week.

Furthermore, it has been surprisingly found that a combination of amuscarinic antagonist, especially of a long-acting muscarinic antagonist(LAMA), preferably a LAMA of the formula I, most preferably LAMA 1 oranother pharmaceutically acceptable salt of the cation thereof, and aglucocorticoid such as ciclesonide or a pharmaceutically acceptable saltthereof is particularly advantageous for the use in a method of treatingan airway disease in equines, preferably horses. An advantage of thepresent invention is the quick onset of the effect after theadministration of the combination.

Additionally, it has been surprisingly found that a (triple) combinationof a muscarinic antagonist, especially of a long-acting muscarinicantagonist (LAMA), preferably a LAMA of the formula I, most preferablyLAMA 1 or another pharmaceutically acceptable salt of the cationthereof, and a glucocorticoid such as ciclesonide or a pharmaceuticallyacceptable salt thereof and optionally/or a long-acting beta-2adrenergic agonist (LABA) or a pharmaceutically acceptable salt thereof,is particularly advantageous for the use in a method of treating anairway disease in equines, preferably horses. An advantage of thepresent invention is the great extent of the effect after theadministration of the (triple) combination.

LAMA 1 improves lung function, increases blood pH and reduces paCO₂,whereas both LABAs and/or LAMAs in general improve lung function andclinical score, whereas ciclesonide improves lung function and clinicalscore as well.

LAMA 1 is currently not approved in equine or any other species.Clenbuterol is approved in equine to be used for treatment of airwaysdiseases accompanied by bronchospasm.

Although both LAMAs and LABAs in general as well as glucocorticoids suchas ciclesonide are used separately as medication against pulmonarydiseases in certain species, it is surprising that the above describedcombination(s) (such as double or triple combinations of LAMAs,glucocorticoids and optionally LABAs or a combination of LAMAs andLABAs, preferably the combination of a LAMA, most preferably LAMA 1, anda glucocorticoid, most preferably ciclesonide) actually leads to a quickand extensive relief during equine pulmonary diseases such as RAO, IADand SPAOPD. Some combinations are known in human medicine for thetreatment of asthma and/or chronic obstructive pulmonary disease (e.g.SYMBICORT® TURBOHALER® containing budesonide and formoterol). However,these combinations have not been shown to be effective in equines suchas horses so far.

The advantage of the above described combination(s) (muscarinicantagonist/LAMA, preferably LAMA 1, and a glucocorticoid, preferablyciclesonide, as well as triple combinations with a LABA or a combinationof a LAMA, preferably LAMA 1, and a LABA) compared to the use of aglucocorticoid such as ciclesonide or budesonide or fluticasone alone isthat the onset of the effect is quick (within minutes after theadministration of the combination).

An additional advantage of the combination therapy (such as thecombinations described above, especially the combination of a LAMA,preferably LAMA 1, and a glucocorticoid, preferably ciclesonide)compared for example to the use of a LAMA alone is that the observed(technical/therapeutic) effect is greater for the combination.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Phase I: Temporal variations of transpulmonary pressure (ΔPL) intwo individual horses (horse ID 312 and 91) following a singleadministration of 800 μg LAMA 1.

FIG. 2: Phase I: Temporal variations of lung resistance (RL) in twoindividual horses (horse ID 312 and 91) following a singleadministration of 800 μg LAMA 1.

FIG. 3: Phase I: Temporal variations of lung elastance (EL) in twoindividual horses (horse ID 312 and 91) following a singleadministration of 800 μg LAMA 1.

FIG. 4: Phase IV—period 1: Temporal variations of transpulmonarypressure (ΔPL) in two individual horses (horse ID 40 and 91) following asingle administration of 2000 μg LAMA 1 (20 puffs, 100 μg/puff inaqueous formulation).

FIG. 5: Phase IV—period 1: Temporal variations of lung resistance (RL)in two individual horses (horse ID 40 and 91) following a singleadministration of 2000 μg LAMA 1 (20 puffs, 100 μg/puff in aqueousformulation).

FIG. 6: Phase IV—period 1: Temporal variations of lung elastance (EL) intwo individual horses (horse ID 40 and 91) following a singleadministration of 2000 μg LAMA 1 (20 puffs, 100 μg/puff in aqueousformulation).

FIG. 7: Phase IV—period 2: Temporal variations of transpulmonarypressure (ΔPL) in two individual horses (horse ID 40 and 91) following asingle administration of 2000 μg LAMA 1 (4 puffs, 500 μg/puff inethanolic formulation).

FIG. 8: Phase IV—period 2: Temporal variations of lung resistance (RL)in two individual horses (horse ID 40 and 91) following a singleadministration of 2000 μg LAMA 1 (4 puffs, 500 μg/puff in ethanolicformulation).

FIG. 9: Phase IV—period 2: Temporal variations of lung elastance (EL) intwo individual horses (horse ID 40 and 91) following a singleadministration of 2000 μg LAMA 1 (4 puffs, 500 μg/puff in ethanolicformulation).

FIG. 10: Phase IV—period 3: Temporal variations of transpulmonarypressure (ΔPL) in two individual horses (horse ID 40 and 91) following asingle administration of 2000 μg LAMA 1 (20 puffs, 100 μg/puff inethanolic formulation).

FIG. 11: Phase IV—period 3: Temporal variations of lung resistance (RL)in two individual horses (horse ID 40 and 91) following a singleadministration of 2000 μg LAMA 1 (20 puffs, 100 μg/puff in ethanolicformulation).

FIG. 12: Phase IV—Period 3: Temporal variations of lung elastance (EL)in two individual horses (horse ID 40 and 91) following a singleadministration of 2000 μg LAMA 1 (20 puffs, 100 μg/puff in ethanolicformulation).

FIG. 13: Phase II: Temporal variations in breathing effort scoreassociated with the administration of clenbuterol (black bars) and threedifferent doses of LAMA 1 (2 puffs: 200 μg (white bars), four puffs: 400μg (light grey bars) and 8 puffs: 800 μg (dark grey bars) between days 1and 7 (mean±SEM) (n=8), where SEM is “Standard Error of theMean”.*Significantly different.

FIG. 14: Phase II: Temporal variations in transpulmonary pressure (ΔPL)associated with the administration of clenbuterol (black bars) and threedifferent doses of LAMA 1 (2 puffs: 200 μg (white bars), four puffs: 400μg (light grey bars) and 8 puffs: 800 μg (dark grey bars) between days 1and 7 (mean±SEM) (n=8), where SEM is “Standard Error of the Mean”.

FIG. 15: Phase II: Temporal variations in lung elastance (EL) associatedwith the administration of clenbuterol (black bars) and three differentdoses of LAMA 1 (2 puffs: 200 μg (white bars), four puffs: 400 μg (lightgrey bars) and 8 puffs: 800 μg (dark grey bars) between days 1 and 7(mean±SEM) (n=8), where SEM is “Standard Error of the Mean”.

FIG. 16: Phase II: Temporal variations in lung resistance (RL)associated with the administration of clenbuterol (black bars) and threedifferent doses of LAMA 1 (2 puffs: 200 μg (white bars), four puffs: 400μg (light grey bars) and 8 puffs: 800 μg (dark grey bars) between days 1and 7 (mean±SEM) (n=8), where SEM is “Standard Error of the Mean”.

FIG. 17: Phase II: Temporal variations in transpulmonary pressure (ΔPL)before and 30 minutes after the administration of clenbuterol (blackbars) and three different doses of LAMA 1 (2 puffs: 200 μg (white bars),four puffs: 400 μg (light grey bars) and 8 puffs: 800 μg (dark greybars) on Day 4 (mean±SEM) (n=8), where SEM is “Standard Error of theMean”.

FIG. 18: Phase II: Temporal variations in lung resistance (RL) beforeand 30 minutes after the administration of clenbuterol (black bars) andthree different doses of LAMA 1 (2 puffs: 200 μg (white bars), fourpuffs: 400 μg (light grey bars) and 8 puffs: 800 μg (dark grey bars) onDay 4 (mean±SEM) (n=8), where SEM is “Standard Error of the Mean”.

FIG. 19: Phase II: Temporal variations in lung elastance (EL) before and30 minutes after the administration of clenbuterol (black bars) andthree different doses of LAMA 1 (2 puffs: 200 μg (white bars), fourpuffs: 400 μg (light grey bars) and 8 puffs: 800 μg (dark grey bars) onDay 4 (mean±SEM) (n=8), where SEM is “Standard Error of the Mean”.

FIG. 20: Phase II: Temporal variations in pH of arterial blood samplesassociated with the administration of clenbuterol (black bars) and threedifferent doses of LAMA 1 (2 puffs: 200 μg (white bars), four puffs: 400μg (light grey bars) and 8 puffs: 800 μg (dark grey bars) between days 1and 7 (mean±SEM) (n=8), where SEM is “Standard Error of the Mean”.

FIG. 21: Phase II: Temporal variations in paCO₂ of arterial bloodsamples associated with the administration of clenbuterol (black bars)and three different doses of LAMA 1 (2 puffs: 200 μg (white bars), fourpuffs: 400 μg (light grey bars) and 8 puffs: 800 μg (dark grey bars)between days 1 and 7 (mean±SEM) (n=8), where SEM is “Standard Error ofthe Mean”.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the various aspects of the present invention it shallbe noted that as used herein and in the appended claims, the singularforms “a”, “an”, and “the” include plural reference unless the contextclearly dictates otherwise. Thus, for example, reference to “apreparation” includes a plurality of such preparations reference to the“carrier” is a reference to one or more carriers and equivalents thereofknown to those skilled in the art, and so forth. Unless definedotherwise, all technical and scientific terms used herein have the samemeanings as commonly understood by one of ordinary skill in the art towhich this invention belongs. All given ranges and values may vary by 1to 5% unless indicated otherwise or known otherwise by the personskilled in the art, therefore, the term “about” was omitted from thedescription. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, the preferred methods, devices, and materials are nowdescribed. All publications mentioned herein are incorporated herein byreference for the purpose of describing and disclosing the substances,excipients, carriers, and methodologies as re-ported in the publicationswhich might be used in connection with the invention. Nothing herein isto be construed as an admission that the invention is not entitled toantedate such disclosure by virtue of prior invention. Terms notspecifically defined herein should be given the meanings that would begiven to them by one of skill in the art in light of the disclosure andthe context. As used in the specification, however, unless specified tothe contrary, the following terms have the meaning indicated and thefollowing conventions are adhered to.

Muscarinic Antagonists: The term “muscarinic antagonists” refers to agroup of substances that block the effects of acetylcholine onmuscarinic receptors to reverse airway obstruction [Barnes, 2004].Therefore “muscarinic antagonists” are also often denoted as“anticholinergics” or “anticholinergic agents”.

Examples for muscarinic antagonists include ipratropium bromide (whichis often administered in equine medicine), atropine, aclidinium bromide,umeclidinium and glycopyrrolate.

The following subgroups of muscarinic antagonists can be defined:

-   -   1. long-acting muscarinic antagonists” or “LAMAs”;    -   2. short-acting muscarinic antagonists” or “SAMAs”.

An example of a LAMA is glycopyrrolate. An example of a SAMA isatropine.

The term “long-acting muscarinic antagonists” or “LAMAs” refers to agroup of substances that block the effects of acetylcholine onmuscarinic receptors for a longer period of time. Examples for LAMAsinclude tiotropium bromide or anticholinergics of the following generalformula I:

wherein

-   A denotes a double-bonded group selected from among

-   X— denotes an anion with a single negative charge,-   R¹ and R² denote C₁-C₄-alkyl, which may optionally be substituted by    hydroxy or halogen;-   R³, R⁴, R⁵ and R⁶, which may be identical or different, denote    hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF3, CN, NO2 or    halogen;-   R7 denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy,    C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH,    CF3, —C₁-C₄-alkylene-C₁-C₄-alkyloxy, —O—COC₁-C₄-alkyl,    —O—COC₁-C₄-alkyl-halogen, —O—COCF₃ or halogen, optionally in the    form of the individual optical isomers, mixtures of the individual    enantiomers or racemates thereof, while if A denotes

-   R¹ and R² denote methyl and-   R³, R⁴, R⁵ and R⁶ denote hydrogen,-   R⁷ cannot also be hydrogen.

Anticholinergics of the general formula I and processes for preparingthem are disclosed for example in WO02/32899, which is herebyincorporated therein.

LAMA 1: The term “LAMA 1” describes a novel anticholinergic agent withthe chemical name (1α,2β,4β,5α,7β)-3-Oxa-9-azoniatricyclo[3.3.1.0^(2,4)]nonane, 9,9-dimethyl-7-(1-oxo-2,2-diphenylpropoxy)-bromide oralternatively (short name) scopine 2,2-diphenylpropionate methobromide.

LAMA 1 (=scopine 2,2-diphenylpropionate methobromide) has the followingchemical structure:

LAMA 1 has the sum formula C₂₄H₂₈NO₃*Br and has a molecular weight of458.39 g/mol.

LAMA 1 is further characterized as follows:

scopine 2,2- Mean Diss. Effects in the diphenyl- K_(D) t1/2 Kallos-Pagelpropionate [nM] [h] Model methobromide Hm3 Hm3 vs. tiotropium

0,4 0,4 3 to 10 fold lower efficacy (acute), 10 fold lower efficacy(chronic), protection over 24 hours (acute and chronic)

Beta-2 Adrenoceptor Agonists: The term “beta-2 adrenoreceptor agonists”or “beta-2 adrenergic agonists” refers to a group of substances thatstimulate β2-adrenergic receptors to relax airway smooth muscles[Tashkin and Fabbri, 2010].

The following subgroups of “beta-2 adrenoreceptor agonists” or “beta-2adrenergic agonists” can be defined:

-   -   1. “long-acting beta-2 adrenergic agonists” or “LABAs”;    -   2. “short-acting beta-2 adrenergic agonists” or “SABAs”.

The term “long-acting beta-2 adrenergic agonists” or “LABAs” refers to asubgroup of substances that stimulate β2-adrenergic receptors to relaxairway smooth muscles for a longer period of time.

Examples for LABAs include salmeterol, formoterol, bambutterol,indacaterol, vilanterol, abediterol and olodaterol hydrochloride.

Examples for beta-2 adrenoreceptor agonists of the SABA type includesalbutamol or albuterol, clenbuterol, pirbuterol and fenoterol.

Glucocorticoids: The term “glucocorticoid” refers to a class of steroidhormones that bind to the glucocorticoid receptor (GR), which is presentin almost every vertebrate animal cell. The name glucocorticoid(glucose+cortex+steroid) derives from its role in the regulation of themetabolism of glucose, its synthesis in the adrenal cortex, and itssteroidal structure.

Glucocorticoids are part of the feedback mechanism in the immune systemthat turns immune activity (inflammation) down. They are therefore usedin medicine to treat diseases caused by an overactive immune system,such as allergies, asthma, autoimmune diseases, and sepsis.

Preferred glucocorticoids according to the present invention areciclesonide and/or budesonide and/or fluticasone.

The term “ciclesonide”((11β,16α)-16,17-[[(R)-Cyclohexylmethylene]bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione,C₃₂H₄₄O₇, M_(r)=540.7 g/mol) is well known in the art andmeans/describes a glucocorticoid used to treat asthma and allergicrhinitis in humans. It is marketed for application in humans under thebrand name ALVESCO® (Takeda GmbH) for asthma and OMNARIS®/OMNAIR®(Takeda GmbH) for hay fever in the US and Canada. Ciclesonide is aprodrug. It is transformed into the active metaboliteC21-C21-desisobutyrylciclesonide (=desciclesonide) via hydrolysis byintracellular esterases in the lung. Ciclesonide is a non-halogenatedglucocorticoid, which predominantly exists in its form as R-Enantiomer.

As used herein the term “prodrug” refers to (i) an inactive form of adrug that exerts its effects after metabolic processes within the bodyconverting it to a usable or active form, or (ii) a substance that givesrise to a pharmacologically active metabolite, although not itselfactive (i.e. an inactive precursor).

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative, carrier or precursor of the parent compound or active drugsubstance which undergoes at least some biotransformation prior toexhibiting its pharmacological effect(s). Such prodrugs either havemetabolically cleavable or otherwise convertible groups and are rapidlytransformed in vivo to yield the parent compound (also called the activemetabolite), for example, by hydrolysis in blood or by activation viaoxidation as in case of thioether groups. Most common prodrugs includeesters and amide analogues of the parent compounds. The prodrug isformulated with the objectives of improved chemical stability, improvedpatient acceptance and compliance, improved bioavailability, prolongedduration of action, improved organ selectivity, improved formulation(e.g., increased hydrosolubility), and/or decreased side effects (e.g.,toxicity). In general, prodrugs themselves have weak or no biologicalactivity and are stable under ordinary conditions. Prodrugs can usuallybe readily prepared from the parent compounds using methods known in theart.

The term “equine” means of or belonging to the family Equidae, whichincludes the horses, asses, and zebras, preferably horses. In addition,the term “equine” encompasses also hybrids of members of the familyEquidae (e.g., mules, hinnies, etc.)

The term “patient” or “subject” embraces mammals such as primatesincluding humans. The term “patient” or “subject” as used herein relatesspecifically to horses, especially horses suffering from airway disease(particularly pulmonary disease), preferably from recurrent airwayobstruction (RAO) also called heaves or equine COPD and/or summerpasture associated obstructive pulmonary disease (SPAOPD) also calledSummer Pasture Associated Recurrent Airway Obstruction (SPARAO) and/orinflammatory airway disease (IAD), most preferably from RAO.

The term “airway disease” in horses means the following: recurrentairway obstruction (RAO) also called heaves or equine COPD, SummerPasture Associated Obstructive Pulmonary disease (SPAOPD), inflammatoryairway disease (IAD), exercise induced pulmonary hemorrhage (EIPH),infectious diseases, chronic interstitial lung disease and upperrespiratory tract functional disorders.

The term “pulmonary disease” means: recurrent airway obstruction (RAO)also called heaves or equine COPD, Summer Pasture Associated ObstructivePulmonary disease (SPAOPD), inflammatory airway disease (IAD), exerciseinduced pulmonary hemorrhage (EIPH), infectious diseases, or chronicinterstitial lung disease.

The term “recurrent airway obstruction (RAO)” in horses means thefollowing: a chronic syndrome of mature horses with reversible airwayobstruction in the stable showing periods of laboured breathing at restduring exacerbation.

The term “Summer Pasture Associated Obstructive Pulmonary disease(SPAOPD)” in horses means the following: a chronic syndrome, whichshares many clinical and pathological similarities with RAO at rest onthe pasture, suggesting similar pathogenesis, however, it is caused bydifferent antigens.

The term “inflammatory airway disease (IAD)” in horses means thefollowing: a chronic syndrome of horses showing poor performance orcoughing or excess tracheal mucus without showing periods of labouredbreathing at rest.

The term “effective amount” as used herein means an amount sufficient toachieve a reduction of airway disease in a horse when ciclesonide isadministered at a dosage as described herein. The progress of thetherapy (improvement of airway disease, particularly pulmonary disease,preferably recurrent airway obstruction (RAO) and/or Summer PastureAssociated Obstructive Pulmonary disease (SPAOPD) and/or inflammatoryairway disease (IAD), most preferably RAO as described herein) can bemonitored by standard airway/pulmonary diagnosis, for example, byclinical examination, airway fluid cytology, endoscopy, lung functionmeasurement, or blood-gas analysis.

The term “pharmaceutically acceptable derivative thereof” means but isnot limited to pharmaceutically acceptable salts, derivatives,metabolites or pro-drugs of a drug. Derivatives as used herein includebut are not limited to, any hydrate forms, solvates, isomers,enantiomers, racemates, racemic conglomerate and the like of thecompound of choice. Suitable pharmaceutically acceptable salts are wellknown in the art and may be formed with an inorganic or organic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, nitric acid, ace-tic acid, glycolic acid, lactic acid, pyruvicacid, malonic acid, succinic acid, glutaric acid, fumaric acid, malicacid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmiticacid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoicacid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonicacid, benzenesulfonic acid and toluenesulfonic acid.

The term “pharmaceutically acceptable excipient (or carrier oradjuvants)” for use with the pharmaceutical composition(s) according tothe present invention include, for example, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, buffer substances, water,salts or electrolytes and cellulose-based substances. This is not acomplete list possible pharmaceutically acceptable carriers, excipientsand/or adjuvants, and one of ordinary skilled in the art would knowother possibilities, which are replete in the art.

A pharmaceutical composition/preparation/medicament according to theinvention may contain solvents such as water and/or ethanol, acidifierssuch as hydrochloric acid, citric acid and/or phosphoric acid, and otherexcipients like preservatives such as benzalkonium chloride or ethanol,or stabilizers such as EDTA, butylhydroxyanisole or butylhydroxytoluene,viscosity modifiers such as hydroxypropyl methyl cellulose, orsolubilizers such as hydroxypropyl-beta-cyclodextrin, or substances tomake the application of the composition more pleasant to the animalssuch as aromas or flavors.

The concentrations of each solvent can range between 1% m/V and 100%m/V, the concentration of the other excipients can range from 0.01% m/Vto 10% m/V.

Administration: Suitable forms for “administration” of LAMA 1 orcombinations of glucocorticoids such as ciclesonide with LAMA 1 or otherLAMAs and/or beta-2 adrenoreceptor agonist such as long-acting beta-2adrenergic agonist (LABAs) are for example inhalation, parenteral ororal administration, preferably inhalation.

In the specific administration via the RESPIMAT® inhaler (BoehringerIngelheim International GmbH) the content of the pharmaceuticallyeffective LAMA 1 should be in the range from 0.2 to 7% m/V, preferably0.3 to 6.0% m/V or 0.4 to 5% m/V of the total composition, i.e. inamounts which are sufficient to achieve the dose range specifiedhereinafter.

When administered by inhalation ciclesonide may be given as an ethanolicsolution or a solution containing a mixture of water and ethanol.Preferably, therefore, pharmaceutical formulations are characterised inthat they comprise ciclesonide according to the preferred aspects above.

It is particularly preferred that the combination is administered viainhalation/ex inhaler, preferably it is administered once or twice aday. The administration of the combination can be performed by oneinhaler containing both components of the combination. In addition, theadministration of the combination can be performed subsequently by twoinhalers, each of them containing one of the components of thecombination. The subsequent administrations can be performed with orwithout a break between the administrations of the individualcomponents. Suitable formulations may be obtained, for example, bymixing LAMA 1 with known excipients, for example water, pharmaceuticallyacceptable organic solvents such as mono- or polyfunction-al alcohols(e.g. ethanol or glycerol), or refrigerants/propellants such ashydrofluoroalkanes (HFA), specifically HFA 227 and HFA 134a. For aliquid formulation, additional excipients for example hydrochloric acidor citric acid to adjust the [H⁺] concentration may be added.

It is especially preferred that LAMA 1 is administered by/via anaqueous/ethanolic droplet inhaler, for example the RESPIMAT® inhaler oranother inhalation device using the RESPIMAT® aerosol-generatingtechnology. Preferably LAMA 1 is administered once or twice a day. Forthis purpose, LAMA 1 has to be made available in a liquid solution whichis suitable for the inhaler.

Most preferably the solvent in the liquid formulation (inhalationsolution) comprises either water alone, or a mixture of <95% V/V ethanoland 5% V/V water, such as 90% V/V ethanol and 10% V/V water.

A further aspect of the present invention is the application of theliquid formulation (inhalation solution) using the RESPIMAT® inhaler oranother inhalation device using the RESPIMAT® aerosol-generatingtechnology. The RESPIMAT® inhaler is disclosed for example in WO97/12687, which is hereby incorporated therein. This inhaler canadvantageously be used to produce the inhalable aerosols according tothe invention. The dose of active substance delivered ex RESPIMAT®inhaler can be calculated from:

-   -   the concentration of active substance in the liquid formulation        [μg/μL],    -   the “delivered volume”, defined as the volume of liquid expelled        from the RESPIMAT® inhaler per actuation [μL]. The delivered        volume ex RESPIMAT® inhaler has been found to be approximately        11 μL, per actuation, according to the following formula:        Dose [μg]=Concentration [μg/μL]·Delivered Volume [μL]

In the context of the present invention the term “dose” means thedelivered dose “ex inhaler”.

In a further aspect of the present invention the composition isadministered via an (equine) inhaler device. Suitable (equine) inhalerdevices comprise for example a pressurized metered dose inhaler (pMDI)or an aqueous/ethanolic droplet inhaler. A specific form of anaqueous/ethanolic droplet inhaler is for example the RESPIMAT® inhaleror another inhalation device using the RESPIMAT® technology. Preferably,the (equine) inhaler device comprises/consists of an aerosol generatingcore based on the RESPIMAT® aerosol-generating technology, and otherparts to adapt the inhaler to equine use. An (equine) inhaler device isdisclosed for example in WO2010149280, which is hereby incorporatedtherein.

In a preferred aspect the composition is an aqueous formulation and isadministered via an (equine) inhaler device.

In a further aspect of the present invention the liquid formulationcomprises one or more of the solvents/propellants: water, ethanol,hydrofluoroalkane(s) such as HFA 227 and HFA 134a, hydrofluoroolefin(s)such as HFO-1234ze, and optionally additional excipients. HFA is anabbreviation for hydrofluoroalkane and HFO is an abbreviation forhydrofluoroolefin.

In addition to formulations containing LAMA 1 alone, additionalcompositions containing in addition a glucocorticoid and/or LABA arepossible. To achieve such a combination formulation a solvent consistingof ethanol in addition to water to increase the solubility of theindividual drug substances can be used. Such a solvent can contain up to95% V/V ethanol and as little as 5% V/V water. Solvents containingethanol have the additional advantage of requiring a lower concentrationor no preservative as combinations of ethanol and water can inhibit thegrowth or kill microorganisms.

The invention relates to muscarinic antagonists (including long actingmuscarinic antagonists (LAMAs)), preferably of the general formula I,more preferably of the formula II (=LAMA 1), for the treatment of airwaydisease, such as pulmonary disease, preferably recurrent airwayobstruction (RAO), summer pasture associated obstructive pulmonarydisease (SPAOPD), and inflammatory airway disease (IAD) in animals suchas equines, preferably horses.

The invention further relates to a combination of a muscarinicantagonists (including long acting muscarinic antagonists (LAMAs),preferably of the general formula I, more preferably of the formula II(=LAMA 1), with a glucocorticoid such as ciclesonide or budesonide,preferably ciclesonide, for the treatment of airway disease, such aspulmonary disease, preferably recurrent airway obstruction (RAO), summerpasture associated obstructive pulmonary disease (SPAOPD), andinflammatory airway disease (IAD) in animals such as equines, preferablyhorses.

The invention further relates to a combination of a muscarinicantagonists (including long acting muscarinic antagonists (LAMAs),preferably of the general formula I, more preferably of the formula II(=LAMA 1), with a glucocorticoid such as ciclesonide or budesonide, andoptionally with beta-2 adrenoceptor agonists (including long actingbeta-2 adrenoceptor agonists (LABAs)) for the treatment of airwaydisease, such as pulmonary disease, preferably recurrent airwayobstruction (RAO), summer pasture associated obstructive pulmonarydisease (SPAOPD), and inflammatory airway disease (IAD) in animals suchas equines, preferably horses.

The invention further relates to a combination of a muscarinicantagonists (including long acting muscarinic antagonists (LAMAs),preferably of the general formula I, more preferably of the formula II(=LAMA 1), with a glucocorticoid such as ciclesonide or budesonide, orwith beta-2 adrenoceptor agonists (including long acting beta-2adrenoceptor agonists (LABAs)) for the treatment of airway disease, suchas pulmonary disease, preferably recurrent airway obstruction (RAO),summer pasture associated obstructive pulmonary disease (SPAOPD), andinflammatory airway disease (IAD) in animals such as equines, preferablyhorses.

Preferably said beta-2 adrenoceptor agonist is salbutamol (albuterol),pirbuterol, clenbuterol, fenoterol, salmeterol, formoterol, indacaterol,vilanterol, abediterol and olodaterol (hydrochloride).

In a further aspect of the present invention the LAMA of the presentinvention is glycopyrrolate, ipratropium bromide, aclidinium bromide,umeclidinium or tiotropium bromide.

The invention specifically concerns a long-acting muscarinic antagonist(LAMA) or another pharmaceutically acceptable salt of the cation thereoffor use as a medicament in an Equine, such as a horse.

The invention concerns a long-acting muscarinic antagonist (LAMA) oranother pharmaceutically acceptable salt of the cation thereof for theuse in a method of treating an airway disease in an equine, preferably ahorse.

Preferably the LAMA is a compound of the general formula:

wherein

-   A denotes a double-bonded group selected from among

-   X— denotes an anion with a single negative charge,-   R¹ and R² denote C₁-C₄-alkyl, which may optionally be substituted by    hydroxy or halogen;-   R³, R⁴, R⁵ and R⁶, which may be identical or different, denote    hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF3, CN, NO2 or    halogen;-   R7 denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy,    C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH,    CF3, —C₁-C₄-alkylene-C₁-C₄-alkyloxy, —O—COC₁-C₄-alkyl,    —O—COC₁-C₄-alkyl-halogen, —O—COCF₃ or halogen, optionally in the    form of the individual optical isomers, mixtures of the individual    enantiomers or racemates thereof, while if A denotes

-   R¹ and R² denote methyl and-   R³, R⁴, R⁵ and R⁶ denote hydrogen,-   R⁷ cannot also be hydrogen.

More preferably the LAMA is a compound of the formula (LAMA 1):

In a specific aspect of the present invention the concentration of LAMA1 ranges between 0.2 to 7% m/V, preferably 0.3 to 6.0% m/V or 0.4 to 5%m/V of the total composition.

The invention concerns a long-acting muscarinic antagonist (LAMA) oranother pharmaceutically acceptable salt of the cation thereof or apharmaceutical composition comprising a LAMA or another pharmaceuticallyacceptable salt of the cation thereof, in combination with aglucocorticoid such as ciclesonide or budesonide or fluticasone(preferably ciclesonide) or a pharmaceutical composition comprisingciclesonide or budesonide or fluticasone or a pharmaceuticallyacceptable salt thereof for use as a medicament in an Equine such as ahorse.

The invention further concerns a long-acting muscarinic antagonist(LAMA) or another pharmaceutically acceptable salt of the cation thereofor a pharmaceutical composition comprising a LAMA or anotherpharmaceutically acceptable salt of the cation thereof, in combinationwith a glucocorticoid such as ciclesonide or a pharmaceuticalcomposition comprising ciclesonide or a pharmaceutically acceptable saltthereof for use in a method of treating an airway disease in an equine,preferably a horse.

In a specific aspect of the present invention the pharmaceuticalcomposition comprising the LAMA is a fixed dose combination/apharmaceutical composition comprising a LAMA or pharmaceuticallyacceptable salts thereof and a glucocorticoid such as ciclesonide orbudesonide or pharmaceutically acceptable salts thereof. A preferredcombination is a LAMA of general formula I, most preferred LAMA1, incombination with ciclesonide or budesonide, preferably ciclesonide.Optionally, said pharmaceutical composition comprising the LAMA and theglucocorticoid additionally contains beta-2 adrenoreceptor agonists,such as a LABA.

In another aspect of the present invention the LAMA and theglucocorticoid are further combined with beta-2 adrenoreceptor agonists,such as a LABA or pharmaceutically acceptable salts thereof. Thesecompounds or part of them may be formulated either as separatepharmaceutical compositions or as fixed dose combinations.

In a preferred aspect of the present invention the LAMA is a compound ofthe general formula:

wherein

-   A denotes a double-bonded group selected from among

-   X— denotes an anion with a single negative charge,-   R¹ and R² denote C₁-C₄-alkyl, which may optionally be substituted by    hydroxy or halogen;-   R³, R⁴, R⁵ and R⁶, which may be identical or different, denote    hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF3, CN, NO2 or    halogen;-   R7 denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy,    C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH,    CF3, —C₁-C₄-alkylene-C₁-C₄-alkyloxy, —O—COC₁-C₄-alkyl,    —O—COC₁-C₄-alkyl-halogen, —O—COCF₃ or halogen, optionally in the    form of the individual optical isomers, mixtures of the individual    enantiomers or racemates thereof, while if A denotes

-   R¹ and R² denote methyl and-   R³, R⁴, R⁵ and R⁶ denote hydrogen, R⁷ cannot also be hydrogen.

Preferably the LAMA is a compound of the formula (LAMA 1):

In a specific aspect of the present invention the concentration of LAMA1 ranges between 0.2 to 7% m/V, preferably 0.3 to 6.0% m/V or 0.4 to 5%m/V of the total composition.

A specific aspect of the present invention is the combination of LAMA 1or a pharmaceutically acceptable salt thereof with ciclesonide or apharmaceutically acceptable salt thereof.

Another specific aspect of the present invention is the combination ofLAMA 1 or a pharmaceutically acceptable salt thereof with budesonide ora pharmaceutically acceptable salt thereof.

A further aspect of the present invention is the combination of LAMA 1or a pharmaceutically acceptable salt thereof with clenbuterol or apharmaceutically acceptable salt thereof.

Another specific aspect of the present invention is the combination ofLAMA 1 or a pharmaceutically acceptable salt thereof with ciclesonide ora pharmaceutically acceptable salt thereof and albuterol/albuterolsulfate or another pharmaceutically acceptable salt thereof.

A further specific aspect of the present invention is the combination ofLAMA 1 or a pharmaceutically acceptable salt thereof with ciclesonide ora pharmaceutically acceptable salt thereof and olodaterol hydrochlorideor another pharmaceutically acceptable salt thereof.

In another specific aspect of the present invention the LAMA istiotropium bromide or a pharmaceutically acceptable salt thereof. Aspecific aspect of the present invention is the combination oftiotropium bromide with ciclesonide and optionally olodaterolhydrochloride.

In a specific aspect of the present invention the airway disease is apulmonary disease. Preferably the airway disease is selected from thegroup consisting of: recurrent airway obstruction (RAO), summer pastureassociated obstructive pulmonary disease (SPAOPD), and inflammatoryairway disease (IAD).

In a further specific aspect of the present invention said LAMA or thepharmaceutical composition comprising the LAMA is (in) a liquidformulation, preferably a partially ethanolic formulation, mostpreferably said liquid formulation is for inhalation.

In another specific aspect of the present invention said LAMA or thepharmaceutical composition comprising the LAMA is administered via an(equine) inhaler device, preferably said inhaler device comprises:

-   -   a. a pressurized metered dose inhaler or an aqueous/ethanolic        droplet inhaler such as the RESPIMAT® inhaler or another        inhalation device using the RESPIMAT® aerosol-generating        technology and    -   b. an adapter for equine use.

In a preferred aspect of the present invention LAMA 1 or apharmaceutically acceptable salt of the cation thereof is administeredat a dose of 100 μg to 3000 μg ex inhaler, 200 μg to 2000 μg ex inhaler,200 μg to 800 μg ex inhaler, preferably at a dose of 200 μg to 800 μg exinhaler.

In another preferred aspect of the present invention ciclesonide or apharmaceutical composition comprising ciclesonide or a pharmaceuticallyacceptable salt thereof is administered at a dose of 100 μg to 5000 μgex inhaler, 450 μg to 3712.5 μg ex inhaler, 900 μg to 3712.5 μg exinhaler, preferably at a dose of 900 μg to 3712.5 μg ex inhaler.

In a further preferred aspect of the present invention the LAMA or thepharmaceutical composition comprising the LAMA is administered once ortwice a day (once or twice daily), preferably once a day.

The invention further concerns a pharmaceutical composition comprising along-acting muscarinic antagonist (LAMA) or pharmaceutically acceptablesalts thereof and a LABA or pharmaceutically acceptable salts thereofand optionally a glucocorticoid such as ciclesonide or budesonide(preferably ciclesonide) or pharmaceutically acceptable salts thereofand optionally a pharmaceutically acceptable excipient.

The invention furthermore concerns a pharmaceutical compositioncomprising a long-acting muscarinic antagonist (LAMA) orpharmaceutically acceptable salts thereof and a glucocorticoid such asciclesonide or budesonide (preferably ciclesonide) or pharmaceuticallyacceptable salts thereof and optionally a LABA or pharmaceuticallyacceptable salts thereof and optionally a pharmaceutically acceptableexcipient.

Preferably said composition is a liquid formulation, most preferably asolution for inhalation.

In a preferred aspect of this invention the LAMA is a compound of thegeneral formula

wherein

-   A denotes a double-bonded group selected from among

-   X— denotes an anion with a single negative charge,-   R¹ and R² denote C₁-C₄-alkyl, which may optionally be substituted by    hydroxy or halogen;-   R³, R⁴, R⁵ and R⁶, which may be identical or different, denote    hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF3, CN, NO2 or    halogen;-   R7 denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy,    C₁-C₄-alkylene-halogen, halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH,    CF3, —C₁-C₄-alkylene-C₁-C₄-alkyloxy, —O—COC₁-C₄-alkyl,    —O—COC₁-C₄-alkyl-halogen, —O—COCF₃ or halogen, optionally in the    form of the individual optical isomers, mixtures of the individual    enantiomers or racemates thereof, while if A denotes

-   R¹ and R² denote methyl and-   R³, R⁴, R⁵ and R⁶ denote hydrogen,-   R⁷ cannot also be hydrogen.

Most preferably the LAMA is a compound of the formula (LAMA 1):

In a specific aspect of the present invention the concentration of LAMA1 ranges between 0.2 to 7% m/V, preferably 0.3 to 6.0% m/V or 0.4 to 5%m/V of the total composition.

The invention further concerns a method of treating an airway disease inan equine, preferably a horse, comprising

-   -   a. administrating a therapeutically effective amount of a LAMA        or a pharmaceutical composition comprising the LAMA or    -   b. administrating a therapeutically effective amount of a        pharmaceutical composition comprising a LAMA or a        pharmaceutically acceptable salt thereof in combination with a        glucocorticoid such as ciclesonide or a pharmaceutically        acceptable salt thereof or    -   c. administrating a therapeutically effective amount of a        pharmaceutical composition comprising a LAMA or a        pharmaceutically acceptable salt thereof in combination with a        beta-2 adrenoreceptor agonists such as a LABA or a        pharmaceutically acceptable salt thereof or    -   d. administrating a therapeutically effective amount of a        pharmaceutical composition comprising a LAMA or a        pharmaceutically acceptable salt thereof in combination with a        glucocorticoid such as ciclesonide or a pharmaceutically        acceptable salt thereof and a beta-2 adrenoreceptor agonists        such as a LABA or a pharmaceutically acceptable salt thereof or    -   e. administrating a therapeutically effective amount of the        pharmaceutical composition according to the invention (fixed        dose combination)        to an equine patient in need thereof, whereby said airway        disease is preferably a pulmonary disease, most preferably said        airway disease is selected from the group consisting of:        recurrent airway obstruction (RAO), summer pasture associated        obstructive pulmonary disease (SPAOPD), and inflammatory airway        disease (IAD). Preferably the LAMA is LAMA 1 or a pharmaceutical        composition comprising LAMA 1 or another pharmaceutically        acceptable salt of the cation thereof.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

The following examples 1 to 6 give examples of compositions which arepossible to be administered using an inhaler based on the RESPIMAT®spray generating technology.

Example 1

LAMA 1 can be formulated either as an aqueous solution or as anethanolic solution. This first table shows examples for an aqueoussolution:

TABLE 1 Concentration [g/100 mL] Component 0.446% 0.844% LAMA 1 0.4460.844 0.541 1.022 Benzalkonium chloride 0.010 0.010 Edetate disodium0.010 0.010 HCl (0.1 M) ad pH 4.0 ad pH 4.0 Water ad 100.0 mL ad 100.0mLwhere the concentration of hydrogen ions [H⁺] can be measured, forexample, by potentiometric titration.

Example 2

LAMA 1 can be formulated either as an aqueous solution or as anethanolic solution. This second table shows an example of formulationsfor an ethanolic solution with 50% V/V ethanol

TABLE 2 Concentration [g/100 mL] Component 0.844% 4.22% LAMA 1 0.8444.22 1.022 5.11 HCl (0.1 M) 0.1  0.1  corresponds to -log₁₀ c_(H) ⁺ 4.0 4.0  50% V/V ethanol/water ad 100.0 mL ad 100.0 mL

Example 3

The next table shows an example of LAMA 1 formulations for an ethanolicsolution with 90% V/V ethanol:

TABLE 3 Concentration [g/100 mL] Component 0.844% 4.22% LAMA 1 0.8444.22 1.022 5.11 HCl (0.1 M) 0.1  0.1  equivalent to -log₁₀ c_(H) ⁺ 4.0 4.0  90% V/V ethanol/water ad 100.0 mL ad 100.0 mL

Example 4

LAMA 1 can be formulated as an ethanolic combination formulation withbudesonide as shown in the following table 4:

TABLE 4 Concentration [g/100 mL] Component 0.844%/1.810% 4.22%/1.810%LAMA 1 0.844 4.22  1.022 5.11  Budesonide 1.810 1.810 Edetate disodium0.001 0.001 HCl (0.1 M) 0.1  0.1  equivalent to -log₁₀ c_(H) ⁺ 4.0  4.0 90% V/V ethanol/water ad 100.0 mL ad 100.0 mL

Example 5

LAMA 1 can be formulated as an ethanolic combination formulation withciclesonide as shown in the following table 5:

TABLE 5 Concentration [g/100 mL] Component 0.844%/3.00% 4.22%/1.810%LAMA 1 0.844 4.22 1.022 5.11 Ciclesonide 3.00  3.00 Butylhydroxytoluene0.05  0.05 HCl (0.1 M) 0.1  0.1  equivalent to -log₁₀ c_(H) ⁺ 4.0  4.0 90% V/V ethanol/water ad 100.0 mL ad 100.0 mL

Example 6

LAMA 1 can be formulated as an ethanolic combination formulation withciclesonide and albuterol sulfate as shown in the following

TABLE 6 Concentration [g/100 mL] Component 0.84%/3.00%/0.88%4.22%/3.00%/0.88% LAMA 1 0.84 4.22 1.02 5.11 Ciclesonide 3.00 3.00Albuterol 0.88 0.86 corresponds to albuterol sulfate 1.06 1.06Butylhydroxytoluene 0.1  0.1  HCl (0.1M) 0.4  0.4  equivalent to -log₁₀c_(H) ⁺ 3.4  3.4  90% V/V ethanol/water ad 100.0 mL ad 100.0 mL

Example 7 Monotherapy with LAMA 1

LAMA 1 is investigated in a study with 4 phases.

LAMA 1 is used in the formulations as described in examples 1 and 2.

Phase I and IV:

LAMA 1 is investigated in two RAO horses at different phases or periodsas part of a mouldy hay challenge study. The horses are challenged everyday by exposure to mouldy hay. LAMA 1 is administered via the EquineInhaler device at different doses or formulations. Lung functionparameters (change in transpulmonary pressure (ΔPL), lung resistance(RL) and lung elastance (EL)) are measured for 24 h. A singleadministration of 800 μg LAMA 1 (8 actuations in aqueous formulation) isperformed per inhalation to two RAO horses (ID numbers: 312 and 91) inphase I. Two RAO horses are treated with LAMA 1 in phase IV (ID numbers:40 and 91), which can be divided into three periods. 2000 μg LAMA 1 (20actuations in aqueous formulation) is administered per inhalation inperiod 1. 2000 μg LAMA 1 (4 actuations in ethanolic formulation) isadministered per inhalation in period 2. 2000 μg LAMA 1 (20 actuationsin ethanolic formulation) is administered per inhalation in period 3.

A decrease is observed in the lung function variables starting 5 minutesafter the administration of LAMA 1. The values continue to drop until2-8 h depending on the lung function parameter, and the dose orformulation of LAMA 1. The lung function variables are below or reachthe pre-treatment values at 24 h after the single administration of LAMA1 (Phase I: FIGS. 1-3; Phase IV, period 1: FIGS. 4-6; Phase IV, period2: FIGS. 7-9; Phase IV, period 3: FIGS. 10-12).

Phase II:

LAMA 1 is investigated in a cross-over, blinded mouldy hay challengestudy. 8 RAO horses are examined in the study, which is divided into anacclimation and a treatment phase. Placebo for LAMA 1 is administeredonce daily per inhalation via the Equine Inhaler device to all horsesfor 1 week in the acclimation period. LAMA 1 and clenbuterol areadministered to the horses in a cross-over design in the treatmentphase. The horses are challenged by exposure to mouldy hay throughoutthe acclimation and treatment phases. LAMA 1 is administered with thedoses of 200 μg (2 actuations)/400 μg (4 actuations)/800 μg (8actuations)/horse (ex-RESPIMAT®) once daily for 7 days per inhalationvia the Equine Inhaler device. Nozzle A and a commercially availableRESPIMAT® is used in the study. Clenbuterol is administered with a doseof 0.8 μg/kg per os, twice daily for 7 days. Lung function variables(change in transpulmonary pressure (ΔPL), lung resistance (RL) and lungelastance (EL)), breathing effort score, Borborygmi score, blood gasanalysis are examined during the study.

Placebo treatment does not induce significant changes on breathingeffort score, lung function variables (change in transpulmonary pressure(ΔPL), lung resistance (RL) and lung elastance (EL)), pH, paCO₂ andpaO₂. Clenbuterol treated horses have significantly smaller breathingeffort scores on study day 6 than horses treated with 2 or 4 actuationsof LAMA 1 (FIG. 13). None of the treatments (LAMA 1 or clenbuterol)alters significantly ΔPL and EL values over time (Days 4 and 8 comparedto Day 1) (FIGS. 14 and 15). RL values are significantly reduced overtime in the clenbuterol and 800 μg LAMA 1 groups (FIG. 16). Lungfunction variables are measured before and 30 min after theadministration of LAMA 1 on day 4. When compared with pre-treatmentvalues, a decrease in ΔPL, RL and EL is seen in all LAMA 1 groups at 30min after the administration (FIG. 17-19). The change in ΔPL and EL isstatistically significant after the administration of 200 and 400 μgLAMA 1. pH increases and paCO₂ reduces significantly in arterial bloodin the 800 μg LAMA 1 group on Day 7 compared to Day 0 (FIGS. 20 and 21).

Phase III:

A single administration of 800 μg LAMA 1 (8 actuations in aqueousformulation) is performed per inhalation to two healthy horses in phaseIII. Subsequently, ECG measurements are done for 48 h. Physiologicalarrhythmias are noted in both horses before and following theadministration of LAMA 1. Only one observation is classified as either afirst-degree heart block with aberrant intraventricular repolarization,or an artifact due to the movement of the electrodes.

Example 8

The combination of LAMA 1 and ciclesonide is investigated in a mouldyhay challenge model. 8 RAO horses are treated via inhalation using theEquine Inhaler device. Treatment with LAMA 1 monotherapy (maximum 2000μg per administration), with ciclesonide monotheraphy (maximum 3212.5 μgper administration) and with the combinations of LAMA 1 and ciclesonide(maximum dose of LAMA 1 is 2000 μg per administration and the maximumdose of ciclesonide is 3712.5 μg per administration) is examined in thestudy. Lung function variables (change in transpulmonary pressure (ΔPL),lung resistance (RL) and lung elastance (EL)) and weighted clinicalscore is measured in the study.

An improvement in lung function variables and weighted clinical score isobserved in all treatment groups with varying extent. Similarly, theonset of the action shows difference among the treatment groups startingalready a few minutes after drug administration.

REFERENCES

-   -   1. Kutasi O., Balogh N., Lajos Z., Nagy K., Szenci O. Diagnostic        approaches for the assessment of equine chronic pulmonary        disorders. J. Eq. Vet. Sci. (2011) 31: 400-410    -   2. Coutil L. L, Hoffman A. M., Hodgson J., Buechner-Maxwell V.,        Viel L., Wood J. L. N. and Lavoie J.-P.: Inflammatory airway        disease of horses. J. Vet. Intern. Med. (2007) 21: 356-361    -   3. Dauvillier J., Felippe M. J. B., Lunn D. P., Lavoie-Lamoureux        A., Leclere M., Beauchamp G., Lavoie J.-P.: Effect of long-term        fluticasone treatment on immune function in horses with        heaves. J. Vet. Intern. Med. (2011) 25: 549-557    -   4. Tashkin D. P. and Fabbri L. M.: Long-acting beta-agonists in        the management of chronic obstructive pulmonary disease: current        and future agents. Resp. Research (2010) 11:149    -   5. Barnes P. J.: The role of anticholinergics in chronic        obstructive pulmonary disease. Am J Med (2004) 117 (Suppl 12A):        24S-32S.

The invention clamed is:
 1. A method of treating an airway disease in anequine, comprising administering to the equine a composition comprisinga long-acting muscarinic antagonist (LAMA) or another pharmaceuticallyacceptable salt of the cation thereof.
 2. The method according to claim1, wherein the LAMA is a compound of the general formula:

wherein A denotes a double-bonded group selected from among

X— denotes an anion with a single negative charge, R¹ and R² denoteC₁-C₄-alkyl, which may optionally be substituted by hydroxy or halogen;R³, R⁴, R⁵ and R⁶, which may be identical or different, denote hydrogen,C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF3, CN, NO2 or halogen; R7denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, C₁-C₄-alkylene-halogen,halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH, CF3,—C₁-C₄-alkylene-C₁-C₄-alkyloxy, —O—COC₁-C₄-alkyl,—O—COC₁-C₄-alkyl-halogen, —O—COCF₃ or halogen, optionally in the form ofthe individual optical isomers, mixtures of the individual enantiomersor racemates thereof, while if A denotes

R¹ and R² denote methyl and R³, R⁴, R⁵ and R⁶ denote hydrogen.
 3. Themethod according to claim 2, wherein the concentration of LAMA rangesbetween 0.2 to 7% m/V of the composition.
 4. The method according toclaim 2, wherein the concentration of LAMA ranges between 0.3 to 6.0%m/V of the composition.
 5. The method according to claim 2, wherein theconcentration of LAMA ranges between 0.4 to 5% m/V of the composition.6. A method of administering a medicament to an animal, the methodcomprising administering to the animal a composition comprising along-acting muscarinic antagonist (LAMA) or another pharmaceuticallyacceptable salt of the cation thereof in combination with aglucocorticoid.
 7. The method according to claim 6, wherein the animalis a mammal.
 8. The method according to claim 7, wherein the mammal isan equine.
 9. The method according to claim 6, wherein saidglucocorticoid is ciclesonide or budesonide or a pharmaceuticallyacceptable salt thereof.
 10. The method according to claim 9, whereinsaid glucocorticoid is ciclesonide.
 11. The method of claim 8, whereinthe method of administering further comprises a method for treating theequine for an airway disease.
 12. The method according to claim 11,wherein said glucocorticoid is ciclesonide, budesonide, orpharmaceutically acceptable salts thereof.
 13. The method according toclaim 11, wherein said composition further comprises a beta-2adrenoreceptor agonist.
 14. The method according to claim 13, whereinsaid beta-2 adrenoreceptor agonist is a long-acting beta-2 adrenergicagonist (LABA) or a pharmaceutically acceptable salt thereof.
 15. Themethod according to claim 11, wherein said pharmaceutical compositionfurther comprises a pharmaceutically acceptable excipient.
 16. Themethod according to claim 11, wherein the LAMA is a compound of thegeneral formula:

wherein A denotes a double-bonded group selected from among

X— denotes an anion with a single negative charge, R¹ and R² denoteC₁-C₄-alkyl, which may optionally be substituted by hydroxy or halogen;R³, R⁴, R⁵ and R⁶, which may be identical or different, denote hydrogen,C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, CF3, CN, NO2 or halogen; R7denotes hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, C₁-C₄-alkylene-halogen,halogen-C₁-C₄-alkyloxy, C₁-C₄-alkylene-OH, CF3, —C₁-C₄-alkylene-C₁-C₄-alkyloxy, —O—COC₁-C₄-alkyl, —O—COC₁-C₄-alkyl-halogen,—O—-COCF₃ or halogen, optionally in the form of the individual opticalisomers, mixtures of the individual enantiomers or racemates thereof,while if A denotes

R¹ and R² denote methyl and R³, R⁴, R⁵ and R⁶ denote hydrogen.
 17. Themethod according to claim 16, wherein the airway disease is a pulmonarydisease, preferably the airway disease is selected from the groupconsisting of: recurrent airway obstruction (RAO), summer pastureassociated obstructive pulmonary disease (SPAOPD), and inflammatoryairway disease (IAD).
 18. The method according to claim 17, wherein saidLAMA or the composition comprising the LAMA is in a liquid formulation.19. The method according to claim 18, wherein said liquid formulation isa partially ethanolic formulation.
 20. The method according to claim 18,wherein said liquid formulation is for inhalation.
 21. The methodaccording to claim 1, wherein said LAMA or the pharmaceuticalcomposition comprising the LAMA is administered via an inhaler devicecomprising: a. a pressurized metered dose inhaler or an aqueous/ethanolic droplet inhaler; and b. an adapter for equine use.
 22. Themethod according to claim 21, wherein said LAMAor the pharmaceuticalcomposition comprising the LAMA is administered as an aerosol via theinhaler device.
 23. The method according to claim 21, wherein said LAMAor a pharmaceutically acceptable salt of the cation thereof isadministered at a dose of 100 μg to 3000 μg ex inhaler.
 24. The methodaccording to claim 21, wherein said dose is 200 μg to 2000 μg exinhaler.
 25. The method according to claim 21, wherein said dose is 200μg to 800 μg ex inhaler.
 26. The method according to claim 21, whereinciclesonide or a pharmaceutically acceptable salt thereof isadministered at a dose of 100 μg to 5000 μg ex inhaler.
 27. The methodaccording to claim 21, wherein the dose is 450 μg to 3712.5 μg exinhaler.
 28. The method according to claim 21, wherein the dose is 900μg to 3712.5 μg ex inhaler.
 29. The method according to claim 1, whereinsaid composition is administered once or twice a day.
 30. The methodaccording to claim 1, wherein the LAMA is a compound of the formula(LAMA 1):


31. The method according to claim 11, wherein the LAMA is a compound ofthe formula (LAMA 1):